Preparation of 5-beta-(m-hydrocar-bonoxy-phenyl)-ethyl-octalone-1



United States Patent PREPARATION OF S-BETA-(M-HYDROCAR- BONOXY-PHENYL)-ETHYL-0CTALONE-1 William S. Johnson, Madison, Wis., and Dilip K. Banerjee, Calcutta, India No Drawing. Original application August 8, 1950, Serial No. 178,357. Divided and this application September 5, 1952, Serial No. 308,944

13 Claims. (Cl. 260-590) The present invention relates to chemical processes and resulting products, and more particularly to improved processes and novel intermediates having utility in the hormone field. The processes and products of the present invention, for example, may be used in the total synthesis of estrone. See Johnson, Banerjee, Schneider and Gutsche, J. Am. Chem. Soc. 72, 1426 (1950).

The processes of the present invention may be illustrated by the following formulas:

n O-C=CH m A '-'CHR1 VII m-Methoxyacetophenone.-To a stirred solution of 102 g. of m-hydroxyacetophenone in 245 ml. of 15% potassium hydroxide at 55 C. was added 94.5 g. of dimethyl sulfate at such a rate that the temperature was maintained at 60-65 C. The reaction mixture was next 'treated with further quantities of 124 ml. of 15% potasv for thirteen hours.

sium hydroxide and 47.5 g. of dimethyl sulfate with alternate additions of equivalent quantities of each of the reagents successively in six equal portions; the temperature being maintained at 60 C. throughout the addition. A solution of 76 g. of potassium hydroxide in 200 ml. of water was then added and the mixture was heated on a steam bath with stirring for one hour. The cooled reaction mixture was twice extracted with ether and the ethereal solution was washed with water and dried by passing through anhydrous sodium sulfate. Ether was removed and the residue distilled, B. P. l30-l32 (16 mm.).

m-Methoxyphenylacetylene (I).-(a) A solution of 94 g. of m-methoxyacetophenone in 25 ml. of dry benzene was treated with 134 g. of phosphorus pentachloride in an ice and water bath with frequent swirling. The reaction mixture was allowed to stand at room temperature (21 C.) with occasional swirling for ten hours, when a dark green solution was obtained. It was then decomposed by slowly pouring into crushed ice and water and thorough shaking. The light yellow heavy oil was extracted with ether and was washed several times with water. On removal of the solvent the crude product was refluxed with 120 g. of potassium hydroxide and 150 ml. of 95% ethanol in an oil bath held at 1 14 C. Water was added to the reaction mixture and the separated oil was taken up in ether. The ethereal layer was washed with saturated sodium chloride solution. Ether was removed and the residue fractionated. A product boiling between 100-102 (14 mm.) was collected which showed positive Beilsteins test. This was then allowed to stand over solid potassium hydroxide for sixteen hours and refractionated through a ten inch Vigreux column over fresh pellets of potassium hydroxide and a fraction boiling between 94100 C. 14 mm.)

was collected. This product was negative to Beilsteins' test.

(b) m-methoxyacetophenone in 15 ml. of benzene was treated with 85 g. of phosphorus pentachloride in the same manner as described above in (a). On working up 64.5 g. of the crude product was refluxed with 35 g. of potassium hydroxide and 80 ml. of 95% ethanol on the steam bath. The reaction mixture was worked up as above and the product thus obtained was retreated with 40 g. of potassium hydroxide and 50 ml. of 95% ethanol in an oil bath held at -126 C. for twelve hours. Isolation and purification was carried out as described before and a product was obtained boiling at l05ll5 (25 mm.), which on redistillation over solid potassium hydroxide through a Vigreux column yielded m-methoxyphenylacetylene, B. P. 94100 14 mm), n 1.5558.

For further purification 57 g. of the above product was distilled through a Fenske column at a reflux ratio of 1:10 and four difierent cuts were collected consisting of (1) 1 g., (2) 13.61 g., (3) 24.7 g. and (4) 10.15 g., B. P. 90-93 (l216 mm.). The second, third and fourth fractions had the constant refractive index n 1.5560. For the next step this purification, however, was found to be unnecessary.

Condensation of m-methoxyphenylacetylene (I) with trans-decalin-I,S-dione (Il).To a solution of 0.9 g. of

potassium in 30 ml. of tert. butyl alcohol (dried over aluminum tert. butoxide) 3.4 g. of m-methoxyphenylacetylene was added slowly in the cold; 5 ml. of tert. butyl alcohol being used for washing. The clear lightly colored solution was transferred to a separatory funnel withthe aid of 10 ml. of tert. butyl alcohol and this was thenadded, within a period of one and one-half hours, to a warm solution (heated to the boiling point) of 4.15 g. of

trans-decalin-1,5-dione (M. P. 163-165 C.) in 50 ml. of

tert. butyl alcohol with stirring and in an atmosphere of nitrogen. An orange color developed, which deepened on allowing the reaction mixture to stand for twelve hours. it was then stirred for a while with a solution of 5 g. of ammonium chloride in 50 ml. of water in the cold, extracted with ether and the organic layer was thoroughly washed with sodium chloride solution. Solvents were removed on a steam bath, finally under diminished pressure. The crude product of titration with ether and petroleum ether (40-60") gave a solid product melting at 68-76". This product after three recrystallizations from ether-petroleum ether (40-60") yielded (a) S-hy-v droxy-S-fl-(m-methoxyphenyl)-ethynyldecalone-1 (ill) as colorless plates, M. P. 83.8-84.8" C.

From the mother liquors of the OL-lSOII1I' after concentration another product could be isolated, melting at 107- 111" C., which after two recrystallizations from etherpetroleum ether (40-60") yielded the ,B-isonier (III) as rectangular prisms, M. P. 116-1166".

Residues left from the mother liquors of the above two isomers were treated with ether in the cold, when a small quantity of a white insoluble product was isolated, M. P. 182-184". On recrystallization from benzene-ether 1,5- dihydroxy 1,5 di-l3(m-methoxyphenyl)-ethynyl-decalin separated out in glistening white crystals, M. P. 188.4- 189.4".

After separation of the high melting dicondcnsation product from the rest of the material by repeated treatment with ether and filtration, a third isomer could be isolated melting at 92-100", which on three recrystallizations from ether-petroleum ether (40-60") was obtained as white crystalline powder, M. P. 99.4-1002". This isomer proved to be the polymorphic form of the a-isorner (M. P. 83.8-84.8").

Condensation of m-methoxyphenylacetylene Wilh cisdecalin-I,5-diane.Condensation was carried out in the same manner as described above with the trans product using potassium m-methoxyphenyl acetylide prepared from 2.66 g. of m-methoxyphenylacetylene, 0.7-8 g. of potassium in 20 ml. of tort. butyl alcohol and 3.34 g. of cis-decalin-l,5-dione (M. P. 79-81") in 20 ml. of tort. butyl alcohol; 25 ml. of tert, butyl alcohol being used for washing down the reactants. The product was worked up in the usual way and the main product, besides the isolation of the high melting dicondensation product, was found to be the isomer melting at 99-100". Mixtures of the trans and cis-decalin-l,5-dione may also be employed satisfactorily in the described synthesis.

5 hydroxy 5 fi-(m-methoxyphenyl )-ethyldecalne-1, (IV).A solution of 0.2877 g. of (0:) S-hydroxy-S-fl- (m-methoxyphenyl)ethynyldecalone-l, (M. P. 83.8- 84.8") in 20 ml. of ethyl acetate was stirred in an atmosphere of hydrogen with 0.1027 g. of palladium charcoal (Mozingo B) catalyst, when 47.7 ml. of hydrogen was absorbed in nineteen minutes; theoretical requirement for one acetylenic bond being 48.4 ml. of hydrogen. The rate of absorption was uniform from beginning to end of the reduction experiment. The catalyst was filtered off after addition of a small quantity of ether, which seemed to help the coagulation of the finely suspended catalyst. Solvents were removed and the colorless gummy residue was allowed to stand at 35". After twelve hours few crystals were formed. On titration of the whole mass with ether-petroleum ether (40-60") it completely solidified. The melting point of 76.8-77.6" was not changed by crystallization from ether-petroleum ether (40-60").

The isomer with M. P. 99.4100.2 also on hydrogenation yielded the same reduction product, checked by mixed melting point.

8) 5 -hydroxy5-fim-methoxyphenyl) -ethynyldecalonel (M. P. 116-1166") was reduced in the same way as described above and a product melting at 89-906" was isolated, which on recrystallization from ether-petroleum ether (40-60") melted at 894-91".

S-fl-(nwnethoxyplzenyl)ethyloctalone-J (V) .(a) Dehydration of (a) 5 hydroxy 5 fl (m-methoxyphenyl) ethyldecalone-l. The hydroxyketone (0.1758 g.) was heated under reflux at -130" in an oil bath for three and one-half hours with 5' ml. of 88% formic acid. Water was added after cooling and the separated gummy material was extracted with ether. The ethereal layer was washed with sodium bicarbonate solution until the aqueous wash was alkaline to litmus and then with water. On removal of the solvent 0.1642 g. of a viscous oil was obtained, which has so far resisted all attempts at inducing crystallization. The product was purified by evaporative distillation at bath temperature 200-215" (0.4 mm) (b) Reduction and dehydration of the gummy residue, left after separation of the crystalline material from the condensation product of m-methoxyphenylacetylene and decalin-l,5-dione, also yielded the same S-fi-(m-methoxyphenyl) ethyloctalone-l. 5.3 grams of such gummy product dissolved in 40 ml. of ethyl acetate was shaken with 1.8 g. of 5% Pd. charcoal (Mozingo B), when 98% of the theoretical amount of hydrogen was absorbed in three hours and twenty-eight minutes. The crude product was dehydrated without further purification by re fluxing with 40 ml. of 88% formic acid for nine hours in an oil bath held at -136". The product was worked up as described above and S-fi-(m-mcthoxyphenyl) ethyloctalone-l (V), B. P. 210-214" (1 mm.) was obtained.

(0) For the preparation of the above unsaturated ketone (V) in comparatively large scale the following method was employed. The crude condensation product, obtained from 27.7 g. of m-methoxyphenylacetylene, 8.1 g. of potassium in 220 ml. of tort. butyl alcohol and 34.8 g. of decalin-1,5-dione in ml. of tort. butyl alcohol, was boiled for ten minutes with 3 g. of Rauey nickel catalyst in ethyl acetate solution and was filtered directly into a pressure bottle for hydrogenation; altogether 100 ml. of ethyl acetate being used. it. was then shaken with 2 g. of Pd. charcoal catalyst (Mozingo B) in an atmosphere of hydrogen at'27 lbs. pressure. The approximately calculated amount of hydrogen was absorbed within thirteen and "one-half hours. The product was worked up and isolated as previously described anal was refluxed with 450 ml. of 88% formic acid for nineteen hours. On working up as described above 42 g. of 54+ (m-methoxyphenyl)ethyloctalone-l, B. P. 202.5-206" (0.2 mm.) was obtained.

1-ket0-8-meth0xy-I,2,3,4,4a,4b, 5, 6, 10b, J1, I2, 1211- dodecahydrochrysene (VI).-Dry hydrochloric acid gas was passed through a solution of 20.2 g. of 5-,9-(1nmethoxyphenyl)ethyloctalone-l in 200 ml. of dry benzene cooled in ice water for one hour. 28 grams of anhydrous aluminum chloride was then added slowly to it with stirring. Stirring was continued at 28 C. for twenty hours and finally at 40-45" for seventy-two hours, at the end of which period a black heavy layer separated out at the bottom. The product was cooled, decomposed with ice and hydrochloric acid and extracted with ether. The ethereal layer was washed successively with strong hydrochloric acid, three times with water, dilute sodium hydroxide solution and with water. The residue left after evaporation of ether was purified by evaporative distilla tion under diminished pressure yielding a yellow glass, B. P. 220-240 (0.2-0.3 mm.).

The yellow glass obtained after evaporative distillation was dissolved in boiling 95% alcohol and allowed to stand in the cold, and a crystalline product melting at 140-156" with previous shrinking was obtained. After three crystallizations from the same solvent 21 product melting at 164-168" was obtained; and on further crystallization from absolute alcohol the or isomer separated as long needles, M. P. 168.4-".

On concentrating the mother liquors of the Ot-lSOmfil' another product melting at a range of 128-133" (shrinks at 127) was obtained, which after three crystallizations from absolute alcohol yielded the 9 isomer as small needles, M. P. 153.4-154.8. or. isomer 134-150.

Piperonylidene derivative of the a isamer.--A warm (heated to boiling point) solution of 1.03 g. of the a isomer (VI), 0.65 g. of piperonal in 55 m1. of absolute alcohol was treated with 6 ml. of potassium hydroxide solution (5 g. of potassium hydroxide in ml. of water) in an Erlenmeyer flask, which was stoppered and kept at 42 C. for four days. The yellow crystals, which separated were filtered oif, washed with alcohol and water, and dried, M. P. 179-484 (shrinks at 175). On crystallization from acetone the pure piperonylidene derivative, M. P. 190.2-l92 (shrinks at 188) was ob tained.

Piperonylidene derivative of B isomer (VlI).--Condensation was carried out in exactly the same manner as described above with 2.0 g. of the B isomer (V1), 1.1 g. of piperonal in 75 ml. of absolute alcohol and 12. ml. of potassium hydroxide solution (10 g. in 20 ml. water). The separated yellow crystals had a M. P. 199- 206.4, and on recrystallization from benzene melted at 2062l0 (previous shrinking). The purest product after three crystallizations from benzene melted at 209- 211.4" (shrinks at 207).

In the formulas, R represents a blocking group such as lower alkyl, e. g., methyl, ethyl, etc.; aralkyl, e. g., benzyl; or aryl, e. g., phenyl. It replaces the hydrogen (H) of the hydroxyl group forming relatively stable methoxy, benzyloxy, phenoxy, etc., groups. Except for blocking (stabilizing) the oxy group during the reactions the R group is of little or no importance. When making a product such as estrone, for example, the R group is finally removed by hydrolysis to provide the desired free OH group. In the illustrative examples R is methyl, forming a methoxy group, but it will be understood that any of the equivalent blocking groups such as referred to above may be employed. The term oxy as used herein includes both the hydroxy and the hydrocarbon-oxy groups disclosed above. The R or bydrocarbon blocking group may contain 1 to 8 carbon atoms with the lower alkyl radicals which form lower alkoxy groups being generally preferred. The R1 in formula VII is also a blocking type group and represents an aryl group such as phenyl, naphthyl, etc. The complete group at the 2position is an aryl methylene group. The exact position of the double bond in the octalone-l group of compound V is not known although investigations show it to be in the position indicated. In any event it is reduced when ring B is formed to make compound VI.

This is a division of Serial Number 178,357, now Patent Number 2,648,679.

Mixed M. P. with the We claim: I

1. The product, S-hydroxy-S-fl-(m-RO-phenyl)- ethynyldecalone-l, where R is a hydrocarbon group containing 1 to 8 carbon atoms.

2. The product, (a) 5-hydroxy5-fi-(m-methoxyphenyl)-ethynyldecalone-l.

3. The product, (,8) S-hydroxy-S-fl-(m-methoxyphem yl) -ethynyldecalone- 1 4. The product, S-hydroxy-S-fi-(m-RO-phenyD-ethyldecalone-l, where R is a hydrocarbon group containing 1 to 8 carbon atoms.

5. The product, (on) S-hydroxy-S-fi-(m-methoxyphenyl)-ethyldecalone-l.

6. The product, (,8) S-hydroxy-S-p-(m-methoxyphenyl)-ethyldecalone-l.

7. The product, 5-;6-(m-RO-phenyl)-ethyloctalone-l, where R is a hydrocarbon blocking group containing 1 to 8 carbon atoms.

8. The product, lone-l.

9. The process which comprises condensing potassium m-RO-phenyl acetylide with decalin-1,5-dione; catalytically hydrogenating the resulting S-hydroxy-S-fi-(m-RO- phenyl)-ethynyldecalone-1; and dehydrating the resulting S-hydroxy-S-B-(m-RO-phenyl)-ethyldecalone-1 by heating with formic acid to form the S-B-(m-RO-phenyD- ethyloctalone-l, where R is a hydrocarbon group containing 1 to 8 carbon atoms.

10. The process which comprises condensing potassium m-methoxyphenyl acetylide with decalin-l, S-dione; catalytically hydrogenating the resulting S-hydroxy-S-fi- (m-methoxyphenyl)-ethynyldecalone-l; and dehydrating the resulting S-hydroxy-S-[S-(m-methoxyphenyl)-ethyldecalone-l by heating with formic acid to form the 5fi (m-methoxyphenyl)-ethyloctalone-1.

11. The process of preparing S-hydroxy-S-B-(m-methoxyphenyl)-ethynyldecalone-l which comprises condens- S-fim-methoxyphenyl -ethyloctaing potassium m-methoxyphenyl acetylide with decalin- 1,5-dione.

12. The process of preparing S-hydroxy-S-fl-(m-methoxyphenyl)-ethyldecalone-1 which comprises catalytically hydrogenating 5-hydroxy-5-;8-(m-methoxyphenyl)-ethynyldecalone-l.

13. The process of preparing S-B-(m-methoxyphenyD- ethyloctalone-l which comprises heating S-hydroxy-S-fl- (m-methoxyphenyl)-ethyldecalone-1 with formic acid.

References Cited in the file of this patent Beilstein: Handbuch der Org. Chemie, vol. VI, 4th ed., 1923, page 587. 

7. THE PRODUCT, 5-B-(M-RO-PHENYL)-ETHYLOCTALONE-1, WHERE R IS A HYDROCARBON BLOCKING GROUP CONTAINING 1 TO 8 CARBON ATOMS. 